Erythroid differentiation of adult hematopoietic progenitor cells requires stimulation by erythropoietin, a hypoxia inducible cytokine that promotes erythroid progenitor cell survival, proliferation, differentiation and hemoglobin production. Erythropoietin binds to its cell surface receptor and induces transcription factors that regulate erythroid gene expression such as the general erythroid transcription factor GATA-1, the basic helix-loop-helix transcription factor, TAL1, and EKLF which is relatively specific for beta-globin expression. Erythropoietin stimulated induction of erythroid transcription factors also activates expression of the erythropoietin receptor that results in increased sensitivity to erythropoietin. DNA binding of TAL1 is required for normal erythropoiesis and we found that TAL1 regulates erythropoietin receptor expression mediated via three conserved E-box binding motifs (CAGCTG) in the erythropoietin receptor 5 untranslated transcribed region. TAL1 increases association of the GATA-1/TAL1/LMO2/Ldb1 transcription activation complex to the region that includes the transcription start site and the 5 GATA and 3 E-box motifs flanking the erythropoietin receptor transcription start site. In erythroid progenitor cells with high expression of erythropoietin receptor, TAL1 binds to the flanking 5 GATA and 3 E-box regions of the erythropoietin receptor promoter and nucleosome phasing shifts to increase the linker region containing the erythropoietin receptor transcription start site and. These data suggest that TAL1 binds to the promoter region contributing to activation of the erythropoietin receptor expression. Forced expression of TAL1 increases erythropoietin receptor expression leading to increased sensitivity to erythropoietin and provides a mechanism contributing to cell expansion during erythropoietin stimulated erythropoiesis.